Individuals with telomere biology disorders (TBDs) like dyskeratosis congenita (DC) are confronted with numerous health issues during their lifetime. TBDs do not always look the same – some people may have symptoms very early in life while others develop their first health problems as adults. Over the last decade, scientific advances have uncovered disease-causing variants (i.e. mutations) in several telomere-related genes. These discoveries have helped us understand some of the reasons why there is such a wide spectrum of complications in TBDs and led us to ask whether we could quantify the extent to which the gene and/or mode of inheritance might affect long term outcomes.

We compiled all available clinical data on the 231 TBD/DC participants enrolled in the inherited bone marrow syndromes study at the National Cancer Institute1 since 2002 and compared it with the affected gene and mode of inheritance2.

The following mode of inheritance were used for comparison:

X-linked recessive (XLR): mutation in a gene on the X chromosome causes the clinical features (phenotypes). It is always expressed in males whereas females carry the mutation but generally do not show symptoms. In TBD/DC the only affected gene known to follow XLR inheritance is DKC1.

Autosomal recessive (AR): two mutations in a gene (one inherited from each parent) must be present for the disease to develop.

Autosomal dominant (AD): one mutation in a gene (inherited from one parent) must be present for the disease to develop. Of note, in several genes (i.e., RTEL1, TERT, ACD, PARN) both AR and AD inheritance have been described.

de novo: present for the first time in one family member as a result of a mutation in the egg or sperm of one of the parents or arises in the fertilized egg itself during early embryogenesis. TINF2 often occurs de novo and was therefore evaluated separately.

We found that patients with TBDs due to TINF2, XLR, or AR inheritance have a higher risk of early onset bone marrow failure and are more likely to present at a young age with symptoms affecting multiple organs – such as skin involvement, neurologic issues, liver or vascular problems. Pulmonary fibrosis without prior bone marrow transplant was more frequently seen in patients with AD TBDs. The fewer medical problems, and later onset of symptoms, are likely the reason why we also found a better overall outcome and overall survival in individuals with AD TBDs.

This study suggests that it may be possible to use a person’s genetic background to guide clinical decisions. For example, patients with DKC1 (only males), TINF2, or AR disease should be observed closely for early development of bone marrow failure and other severe symptoms. However, patients with only one variant (AD) should be aware that complications, such as pulmonary fibrosis, may develop later in life.

Our investigation is only the first step towards individually tailored care for TBD/DC patients and families. Research in larger cohorts is needed to determine how certain genes can be used to specifically guide clinical decisions and surveillance.


2. Niewisch MR, Giri N, McReynolds LJ, et al. Disease progression and clinical outcomes in telomere biology disorders. Blood. 2022;139(12):1807-1819.